Hypoxia‐reduced YAP phosphorylation enhances expression of Mucin5AC in nasal epithelial cells of chronic rhinosinusitis with nasal polyps

Abstract

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.ObjectiveWe investigated the potential role of yes‐associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.MethodsTissue biopsies of CRSwNP (n = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 9) and healthy controls (n = 30) were investigated together with a well‐established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)‐1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.ResultsWe observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF‐1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF‐1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF‐1α facilitated the activation and nuclear localization of active‐YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF‐1α‐mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF‐1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.ConclusionOur findings indicated that hypoxia enhances YAP activation by decreasing p‐LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.